Alzheimer's disease (AD) is a serious neurodegenerative disorder with no effective treatment. Its onset and progression correlate with neuroinflammatory processes [1], and inflammatory microglia are associated with AD-like pathology in a transgenic mouse model [2, 3].
Retinoids are analogues of vitamin A-derived all-trans retinoic acid (ATRA), and are specific modulators of many cellular functions, including immunity [4]. Retinoic acid (RA) exerts its biological actions by binding to its cognate nuclear receptors, retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to regulate transcription of target genes. Each of them has three subtypes: RARα,δ,γ and RXRα,β,γ.
Vitamin A deprivation results in Aβ accumulation in rats [5]. RA increases gene transcription of a disintegrin and metalloprotease, family 10 (ADAM10) [6-8] and increases its α-secretase activity, which cleaves a specific site of amyloid β-protein precursor (AβPP). This cleavage inhibits Aβ generation and leads to release of the soluble neuroprotective protein sAβPPα (9-11). Clinical evidence has indicated that late-onset AD brains have a defect in retinoid transport function [12]. Therefore, RA or synthetic retinoids may be candidates for treatment of AD [5, 13-17]. We previously demonstrated that oral administration of Am80 (0.5 mg/kg/d, for 14 weeks) reduced levels of Tris-buffered saline (TBS)-insoluble Aβ42 in brains of 5-month-old APP23 mice, an AD model [15]. However, that study did not detect behavioral benefits of this treatment. Recently, Cramer et al. [16] reported that the RXR-selective agonist bexarotene enhanced apolipoprotein E-dependent Aα clearance from the brain and improved behavioral deficits in APP/PS1 mice. However, there are conflicting data regarding the therapeutic effect of bexarotene on AβPP mice [18-22]. Furthermore, it remains unclear whether co-activation of RARs with RXRs is required to improve AD pathology and memory deficits.
Retinoids modify T helper (Th) types 1 and 2 cells and regulatory T-cell-associated immune responses in rodents and humans [23]. They also suppress Th1 development and enhance development of naïve CD4 T cells to interleukin (IL)-4-producing Th2 cells [24]. IL-4 plays an essential role in higher functions, such as memory and learning, of normal brain [25]. For example, IL-4-deficient mice show cognitive impairment in spatial learning tasks [26]. However, it remains unclear whether retinoids affect AD-associated neuroinflammatory processes in vivo.